Astrid Gnekow

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97.

PURPOSE The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment. PATIENTS AND METHODS For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI). RESULTS Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 +/- 0.01) and metastases-free survival (rate at 3 years, 0.94 +/- 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy. CONCLUSION Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.

Preradiation chemotherapy for pediatric patients with high-grade glioma

To evaluate the feasibility and efficacy of intensive chemotherapy given prior to irradiation in pediatric patients with malignant glioma, the Society of Pediatric Oncology in Germany started a randomized trial in 1991. The high‐grade glioma strata had to be closed because of insufficient patient accrual. The follow‐up data from these patients are reported.

Current and Future Strategies in Radiotherapy of Childhood Low-Grade Glioma of the Brain

Background:For more than 60 years, radiation therapy has been an integral part in the management of childhood low-grade glioma. As this tumor carries an excellent long-term prognosis, the risk of late effects is of particular clinical importance and impinges upon radiotherapeutic treatment strategies.Material and Methods:Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms.Results:Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e. g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field—four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects.Conclusions:More studies and clear definitions of clinical endpoints such as neurocognitive and endocrinological outcome are needed in order to clarify the impact of radiation therapy on the risk of late sequelae. Presently, the strategy to postpone radiotherapy in the younger children, especially with NF, is justified to reduce the risk of late effects. These information and the contribution of tumor, surgery and chemotherapy will help to define the role of radiation therapy in the future management of childhood low-grade glioma and whether the use of highly sophisticated and expensive treatment techniques is justifiable. The recently initiated prospective study of the APRO (Pediatric Radiooncology Working Party) on documentation of dose prescription to organs at risk and the network of the GPOH to explore late effects as well as the forthcoming prospective SIOP/GPOH (International Society of Pediatric Oncology/German Society of Pediatric Oncology and Hematology) LGG 2003 trial are addressing these issues.Hintergrund:Seit mehr als 60 Jahren bildet die Bestrahlung einen integralen Therapiebestandteil bei der Behandlung von niedrigmalignen Gliomen im Kindesalter. Da diese Tumoren eine sehr gute Langzeitprognose besitzen, spielt das Risiko für Therapiefolgen eine besondere klinische Rolle und beeinflusst damit radiotherapeutische Behandlungsstrategien.Material und Methodik:Studien über die Anwendung von Radiotherapie bei niedrigmalignen Gliomen im Kindesalter wurden systematisch analysiert im Hinblick auf Daten bezüglich strahlentherapieinduzierter Spätfolgen im Hirnparenchym, endokriner Funktion, Wachstum und Entwicklung, neurokognitiver Funktion, Gefäßveränderungen und Zweittumoren.Ergebnisse:Literaturangaben über Späteffekte sind gering und heterogen. Zurückliegende Berichte schlossen nur retrospektive Serien der 30er Jahre bis heute ein, also eine Zeit, in der sich Behandlungsrichtlinien und Strahlentherapietechniken erheblich unterschieden und sich in jüngster Zeit deutlich änderten. Häufig bestand eine ausgeprägte Unsicherheit hinsichtlich des Gesundheitszustands vor Therapie und strahlentherapiebezogener Faktoren (wie Gesamtdosis, Einzeldosis, Bestrahlungsfelder). Trotz dieser Einschränkungen und häufig widersprüchlicher Beobachtungen scheint es, als wiesen insbesondere jüngere Kinder und Kinder mit Neurofibromatose (NF) ein besonderes Risiko für endokrinologische Störungen in Form von Wachstumsverzögerung und Entwicklungsstörungen ebenso wie für neurokognitive Dysfunktionen, ausgedrückt als Probleme in der psychosozialen Umgebung wie Erziehung, Ausbildung und Beruf, auf. Beide Beobachtungen können jedoch dem höheren Anteil von NF bei sehr jungen Kindern zugeschrieben werden, die häufig große Tumoren entlang der gesamten supratentoriellen Mittellinie entwickeln. Das Risiko für strahlentherapieinduzierte Störungen der Visusfunktion ist gering (kein Literaturbericht hierzu). Jüngere Kinder mit NF scheinen ein erhöhtes Risiko für Gefäßerkrankungen aufzuweisen. 33 Fälle von Moyamoya-Syndrom wurden gefunden (vorzugsweise bei sehr jungen Kindern), von denen 18 das klinische Bild einer NF boten. Andere zerebrovaskuläre Ereignisse (24 Fälle, davon 14 NF-positiv) und Zweittumoren (15 Fälle, von denen fünf innerhalb der Bestrahlungsfelder auftraten—vier waren hochmaligne Astrozytome) sind selten. Letztere sind nicht von späten Rückfällen mit Malignisierung zu unterscheiden. Moderne Bestrahlungstechniken scheinen das Risiko für strahlentherapiebedingte Spätfolgen zu senken.Schlussfolgerungen:Weitere prospektive Studien und eine klare Definition klinischer Endpunkte wie neurokognitives und endokrinologisches Behandlungsergebnis sind notwendig, um den Einfluss der Strahlentherapie auf das Risiko für Therapiefolgen abzuklären. Derzeit ist die Strategie, die Strahlentherapie bei jüngeren Kindern hinauszuzögern (besonders bei NF), gerechtfertigt, um das Risiko für Therapiefolgen zu reduzieren. Diese Informationen und der Beitrag von Tumor, Operation und Chemotherapie werden dazu dienen, die Rolle der Strahlentherapie in zukünftigen Behandlungsstrategien zu definieren, und klären helfen, ob die Anwendung hochpräziser und aufwendiger Bestrahlungstechniken gerechtfertigt ist. Die kürzlich initiierte prospektive Studie der APRO (Arbeitsgemeinschaft Pädiatrische Radioonkologie) zur Dokumentation von Dosisverschreibungen innerhalb von Risikoorganen und das Kompetenznetzwerk pädiatrische Onkologie der GPOH zur Untersuchung von Spätfolgen befassen sich ebenso wie die in Vorbereitung befindliche SIOP/GPOH- (International Society of Pediatric Oncology/Gesellschaft für Pädiatrische Onkologie und Hämatologie-)LGG-2003-Studie mit diesen Themen.

Intensive chemotherapy improves survival in pediatric high‐grade glioma after gross total resection: results of the HIT‐GBM‐C protocol

The authors hypothesized that intensified chemotherapy in protocol HIT‐GBM‐C would increase survival of pediatric patients with high‐grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG).

Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part II: Treatment-related late toxicity

Background:For more than 60 years, radiation therapy has been an integral part in the management of childhood low-grade glioma. As this tumor carries an excellent long-term prognosis, the risk of late effects is of particular clinical importance and impinges upon radiotherapeutic treatment strategies.Material and Methods:Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms.Results:Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e. g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field—four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects.Conclusions:More studies and clear definitions of clinical endpoints such as neurocognitive and endocrinological outcome are needed in order to clarify the impact of radiation therapy on the risk of late sequelae. Presently, the strategy to postpone radiotherapy in the younger children, especially with NF, is justified to reduce the risk of late effects. These information and the contribution of tumor, surgery and chemotherapy will help to define the role of radiation therapy in the future management of childhood low-grade glioma and whether the use of highly sophisticated and expensive treatment techniques is justifiable. The recently initiated prospective study of the APRO (Pediatric Radiooncology Working Party) on documentation of dose prescription to organs at risk and the network of the GPOH to explore late effects as well as the forthcoming prospective SIOP/GPOH (International Society of Pediatric Oncology/German Society of Pediatric Oncology and Hematology) LGG 2003 trial are addressing these issues.Hintergrund:Seit mehr als 60 Jahren bildet die Bestrahlung einen integralen Therapiebestandteil bei der Behandlung von niedrigmalignen Gliomen im Kindesalter. Da diese Tumoren eine sehr gute Langzeitprognose besitzen, spielt das Risiko für Therapiefolgen eine besondere klinische Rolle und beeinflusst damit radiotherapeutische Behandlungsstrategien.Material und Methodik:Studien über die Anwendung von Radiotherapie bei niedrigmalignen Gliomen im Kindesalter wurden systematisch analysiert im Hinblick auf Daten bezüglich strahlentherapieinduzierter Spätfolgen im Hirnparenchym, endokriner Funktion, Wachstum und Entwicklung, neurokognitiver Funktion, Gefäßveränderungen und Zweittumoren.Ergebnisse:Literaturangaben über Späteffekte sind gering und heterogen. Zurückliegende Berichte schlossen nur retrospektive Serien der 30er Jahre bis heute ein, also eine Zeit, in der sich Behandlungsrichtlinien und Strahlentherapietechniken erheblich unterschieden und sich in jüngster Zeit deutlich änderten. Häufig bestand eine ausgeprägte Unsicherheit hinsichtlich des Gesundheitszustands vor Therapie und strahlentherapiebezogener Faktoren (wie Gesamtdosis, Einzeldosis, Bestrahlungsfelder). Trotz dieser Einschränkungen und häufig widersprüchlicher Beobachtungen scheint es, als wiesen insbesondere jüngere Kinder und Kinder mit Neurofibromatose (NF) ein besonderes Risiko für endokrinologische Störungen in Form von Wachstumsverzögerung und Entwicklungsstörungen ebenso wie für neurokognitive Dysfunktionen, ausgedrückt als Probleme in der psychosozialen Umgebung wie Erziehung, Ausbildung und Beruf, auf. Beide Beobachtungen können jedoch dem höheren Anteil von NF bei sehr jungen Kindern zugeschrieben werden, die häufig große Tumoren entlang der gesamten supratentoriellen Mittellinie entwickeln. Das Risiko für strahlentherapieinduzierte Störungen der Visusfunktion ist gering (kein Literaturbericht hierzu). Jüngere Kinder mit NF scheinen ein erhöhtes Risiko für Gefäßerkrankungen aufzuweisen. 33 Fälle von Moyamoya-Syndrom wurden gefunden (vorzugsweise bei sehr jungen Kindern), von denen 18 das klinische Bild einer NF boten. Andere zerebrovaskuläre Ereignisse (24 Fälle, davon 14 NF-positiv) und Zweittumoren (15 Fälle, von denen fünf innerhalb der Bestrahlungsfelder auftraten—vier waren hochmaligne Astrozytome) sind selten. Letztere sind nicht von späten Rückfällen mit Malignisierung zu unterscheiden. Moderne Bestrahlungstechniken scheinen das Risiko für strahlentherapiebedingte Spätfolgen zu senken.Schlussfolgerungen:Weitere prospektive Studien und eine klare Definition klinischer Endpunkte wie neurokognitives und endokrinologisches Behandlungsergebnis sind notwendig, um den Einfluss der Strahlentherapie auf das Risiko für Therapiefolgen abzuklären. Derzeit ist die Strategie, die Strahlentherapie bei jüngeren Kindern hinauszuzögern (besonders bei NF), gerechtfertigt, um das Risiko für Therapiefolgen zu reduzieren. Diese Informationen und der Beitrag von Tumor, Operation und Chemotherapie werden dazu dienen, die Rolle der Strahlentherapie in zukünftigen Behandlungsstrategien zu definieren, und klären helfen, ob die Anwendung hochpräziser und aufwendiger Bestrahlungstechniken gerechtfertigt ist. Die kürzlich initiierte prospektive Studie der APRO (Arbeitsgemeinschaft Pädiatrische Radioonkologie) zur Dokumentation von Dosisverschreibungen innerhalb von Risikoorganen und das Kompetenznetzwerk pädiatrische Onkologie der GPOH zur Untersuchung von Spätfolgen befassen sich ebenso wie die in Vorbereitung befindliche SIOP/GPOH- (International Society of Pediatric Oncology/Gesellschaft für Pädiatrische Onkologie und Hämatologie-)LGG-2003-Studie mit diesen Themen.

Treatment of paediatric pontine glioma with oral trophosphamide and etoposide.

To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg m−2 day−1 combined with oral etoposide at 25 mg m−2 day−1 starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies.

Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: Report from the HIT-LGG 1996 trial†‡

We describe demographic data of disseminated childhood low‐grade glioma (DLGG) prospectively recruited in the HIT‐LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series.

Thalamic high-grade gliomas in children: a distinct clinical subset?

Pediatric high-grade gliomas (HGGs) of the thalamic region account for up to 13% of pediatric HGGs and usually result in only anecdotal long-term survival. Because very little is known about these tumors, we aimed to further characterize them. In our series of 99 pediatric thalamic HGGs, there were no significant differences in survival between patients with tumors affecting the thalamus alone (including bithalamic lesions) and patients with tumors affecting the thalamus plus adjacent structures. Tumor resection (event-free survival/overall survival) and an early treatment response to radiotherapy/chemotherapy (event-free survival) had independent prognostic significance, as shown by Kaplan-Meier and multivariate Cox regression analyses. When we compared clinical characteristics and outcomes of pediatric thalamic HGG with those of pediatric (nonthalamic) supratentorial (n = 177) as well as pediatric pontine HGG (including diffuse intrinsic pontine gliomas; n = 234), we found that thalamic HGG shared more similarities with pontine than with supratentorial HGG, but overall, it appeared to represent a clinically distinct subgroup of pediatric HGG. The varying extent of tumor resection in the different tumor localizations may play some role in the observed clinical differences, as shown by multivariate Cox regression analyses, but the tumor site itself was also identified as an independent prognostic parameter. Thus, an additional location-specific effect on survival and/or tumor biology, despite different neurosurgical accessibility, has to be considered. Therefore, future investigations should try to further characterize the obviously site-specific heterogeneity of pediatric HGG on a molecular genetic basis.

Secondary dissemination in children with high-grade malignant gliomas and diffuse intrinsic pontine gliomas

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P=0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered.